Unopposed estrogen therapy in postmenopausal women who have undergone hysterectomy does not appear to raise the risk of breast cancer, in clear contrast to the significant rise in breast cancers among postmenopausal women with intact uteri who take estrogen plus medroxyprogesterone.
However, conjugated equine estrogen (CEE) therapy alone does increase the number of abnormal mammograms requiring follow-up, which includes aspiration and biopsy as well as the attendant emotional and economic costs of each, according to Marcia L. Stefanick, Ph.D., and her associates in the Women's Health Initiative (WHI) study.
The decision to use CEE in postmenopausal women without a uterus, therefore, “should continue to be based on careful consideration of potential risks and benefits for a given individual,” said Dr. Stefanick, a professor of medicine in the prevention research center at Stanford (Calif.) University, and her WHI associates.
The portion of the WHI study that addressed estrogen-only therapy involved 10,739 postmenopausal women aged 50–79 years who had undergone prior hysterectomy and were treated at 40 clinical centers across the United States between 1993 and 1998. The women were randomly assigned to receive either 0.625 mg of CEE (Premarin) or a placebo and were assessed at 6-month intervals.
The study was terminated early in 2004 because interim analysis showed that CEE raised stroke risk without reducing the risk of coronary heart disease. But preliminary analysis of the results up to that date also showed that compared with women taking placebo, those taking CEE had fewer breast cancers. This finding of a possible protective effect prompted an updated analysis, and the WHI investigators now report the results on 237 invasive and 55 in situ breast cancers that developed by the date that subjects were instructed to stop taking their study pills (JAMA 2006;295:1647–57).
In an intention-to-treat analysis, there were nonsignificant reductions in invasive breast cancers and total breast cancers among women taking CEE only, compared with those taking placebo. There was no effect on in situ disease. Further analysis showed that the number of advanced cancers was comparable between the two groups of patients, but there were fewer cases of localized disease in the CEE group.
“In the completed trial database, the invasive breast cancer incidence did not differ significantly between the CEE group and the placebo group,” investigators said.
After 1 year of therapy, the percentage of abnormal mammograms was “substantially higher” in the CEE group (9.2%) than in the placebo group (5.5%). This pattern held constant for each year thereafter, for a cumulative rate of 36.2% in the CEE group and 28.1% in the placebo group.
By the end of the study, women in the CEE group had undergone 198 biopsies or aspirations that yielded negative findings, Dr. Stefanick and her associates noted.
The percentage of mammograms showing “suspicious” rather than simply abnormal findings was similar for both groups, as was the percentage of mammograms that were highly suggestive of malignancy. In contrast to these findings, the results of the CEE plus progesterone portion of the WHI trial showed a definite increase in invasive breast cancers with combined therapy, as well as a definite increase in mammograms deemed “suspicious” or “highly suggestive of malignancy,” they noted.
After 1 year, 9.2% of the women on estrogen and 5.5% in the placebo group had abnormal mammograms. DR. STEFANICK